• Information
  1. Overview of Development of Hyponatremia
  2. Etiology of SIAD
  3. Presentation
  4. Diagnosis
  5. Treatment

A. Overview of Development of Hyponatremia [2]

1. The body PRIMARILY Regulates and Maintains Serum Osmolality
   1. Sensors in the hypothalamus
   2. Sensors in the kidney
   3. Therefore, in normal conditions, total serum osmolarity should be maintained
2. Serum Osmolality (Osm)
   1. Osm=2x[Na+](mM) + (urea nitrogen [mg/dL]÷ 2.8) + (glucose [mg/dL]÷ 18)
   2. Normal Osm is ~280-290 mOsm
   3. Thus, serum [Na+] falls 1.6 mmol/L for every 100mg/dL (5.6 mmol/L) increase in glucose
   4. An increase in serum [Na+] always predicts a hyperosmolar state
   5. A reduction in serum [Na+] may occur with eusomolar
3. Thus, total body sodium depletion OR retention can exist in hyponatremic patients
4. Classifying Hyponatremia
   [Figure] "Evaluation of Hyponatremia"
   1. By volume status of patient: body fluid excess, normal, or deficit
   2. By expansion of intracellular or extracellular or both compartments
   3. By serum Osm in the patient
   4. By total body Na+ level of patient
   5. Elevated glucose and/or urea nitrogen should be ruled out when evaluating hyponatremia
   6. Obtain urine sample for sodium, Urine Osm, creatinine
   7. Calculate fractional excretion of Na+
5. Urine osmolality is >250mOsm in most patients hyponatremia due to medical causes
   1. The "syndrome of inappropriate diuresis" is the most common of hyponatremia
   2. In most cases, an excess of antidiuretic hormone (ADH) is present (see below)
   3. The ADH is actually arginine vasopressin
   4. Not true for primary polydipsia, where urine osmolality ~80mOsm
   5. Not true in persons with normal renal function responding to free water bolus
6. Abnormal [Na+] may occur when water intake exceeds water output (dilution effects)
   1. Manifestation of impaired renal diluting capacity
   2. Usually results from persistent anti-diuretic hormone (ADH) secretion despite depressed serum osmolality
7. Abnormal [Na+] may occur when urinary loss of monovalent cation exceeds intake
   1. Diuretics are a major cause of sodium loss
   2. Most common cause of hyponatremia in developed nations is congestive heart failure (CHF)
   3. CHF associated hyponatremia is usually associated with diuretic use
   4. Gastrointestinal losses of cations occur, but kidney can usually compensate
8. Hyponatremia may also occur from reduction in glomerular filtration rate (GFR)

B. Etiology of SIAD

1. Four Major Categories [1]
   1. Most cases due to inappropriately high levels of ADH, called SIADH
   2. Type A: unregulated secretino of ADH
   3. Type B: elevated basal secretion of ADH
   4. Type C: In a minority of patients, secretion of ADH is suppressed, but at a serum sodium (Na+) level lower than normal; this is called "reset osmostat"
   5. Type D: undetectable levels of ADH
   6. Type D may be caused by gain of function mutation in vasopressin/ADH receptor V2R [3]
2. Central Nervous System (CNS)
   1. Pituitary adenoma
   2. Subdural hematoma / Subarachnoid hemorrhage
   3. Stroke - hemorrhagic > thromboembolic
   4. Encephalitis / Tuberculous meningitis / Bacterial Meningitis
   5. CNS Lupus Erythematosus
   6. Acute Intermittent Porphyria
3. Ectopic ADH (Paraneoplastic)
   1. Small Cell Lung Carcinoma
   2. Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma, Reticulum Cell Sarcoma
   3. Pancreatic Carcinoma
   4. Breast Carcinoma
   5. Duodenal Carcinoma
   6. Thymoma
4. Pulmonary Process
   1. Pneumonia, Empyema, Lung Abscess
   2. Viral Pneumonitis
   3. Chronic obstructive pulmonary disease (COPD)
   4. Tuberculosis
5. Drugs
   1. Tricyclic Antidepressants
   2. Narcotics
   3. Carbamazepine (Tegretol®)
   4. Cyclophosphamide, Vincristine, Vinblastine
   5. Oxytocin
   6. General Anesthesia
6. Other
   1. Any surgery, especially Neurosurgery
   2. Hypothyroidism
   3. Positive pressure respiration
7. IL-6 production may be a major common pathway for induction of SIADH [4]

C. Presentation

1. Hyponatremia
   1. Fatigue, Malaise
   2. Mental Status Changes
2. Mild Fluid Overload

D. Diagnosis

1. Serum Osm low (<275mOsm/kg water) with low Serum Na+
2. Urine Osm >100 mOsm/kg water during hypotonicity
3. Urine sodium >20-40mM and Urine Osm > Serum Osm
4. Clinical euvolemia or slight hypervolemia without edema or ascites
5. Patient must be euvolemic or slightly hypervolemic and no recent use of diuretics
6. Cardiac, Hepatic, Adrenal, Renal, Thyroid (mnemonic "CHART") function must be normal
7. Plasma ADH may be obtained
   1. Quantitative tests are now excellent
   2. Elevated plasma ADH levels despite presence of hypotonicity and clinical euvolemia
8. Supplemental Features
   1. Plasma uric acid <4mg/dL
   2. BUN <10mg/dL
   3. Fractional Na+ excretion >1%
   4. Failure to correct hyponatremia after 0.9% saline infusion
   5. Correction of hyponatremia with fluid restriction

E. Treatment

1. Elimination of underlying cause is the only definitive treatment
2. For treatment of hyponatremia associated with SIAD:
   1. Fluid Restriction: total 1-1.5 L per day total fluid intake
   2. Furosemide to further remove fluid in volume overload patients (rarely needed)
   3. Saline infusion as needed
3. Saline: Hypertonic (3%) or Normal (0.9%) Saline
   1. Determine sodium deficit
   2. Must give a solution with Osm (solution) > Urine Osm
   3. Therefore, Hypertonic Saline is the agent of choice for Urine Osm >300mOsm
   4. Otherwise, isotonic (normal) saline may be used
4. Conivaptan [5]
   1. Vasopressin (ADH) V2 receptor antagonist
   2. FDA approved for euvolemic and hypervolemic hyponatremia, including SIADH
   3. Intravenous infusion given
   4. Potent inhibitor of CYP3A4
5. Demeclocycline (a tetracycline analog) may be used to block ADH effects

References

1. Ellison DH and Berl T. 2007. NEJM. 356(20):2064
2. Fraser CL and Arieff AI. 1997. Am J Med. 102(1):67
3. Steele A, Gowrishankar M, Abrahamson S, et al. 1997. Ann Intern Med. 126(1):20
4. Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. 1998. Ann Intern Med. 128(2):127
5. Conivaptan. 2006. Med Let. 48(1237):51